Developing new therapeutic strategies that damage tumour cells without harming normal tissues is among the primary obstacles in chemotherapy. In this study, a novel β-glucuronidase-sensitive albumin-binding prodrug was designed and synthesized to selectively deliver the drug SN38 to tumour sites and maximize its efficacy. After intravenous administration, the prodrug Mal-glu-SN38 covalently bound to plasma albumin through the Michael addition, enabling it to accumulate in the tumour and release SN38 when triggered by extracellular β-glucuronidase. Compared to irinotecan, Mal-glu-SN38 displayed a slower plasma clearance and increased drug exposure over time. Moreover, Mal-glu-SN38 caused an increase in tumour-site accumulation of both the albumin-prodrug conjugate and free SN38 released from albumin conjugate when compared with irinotecan. After administration of multiple doses, Mal-glu-SN38 also significantly delayed the tumour growth, resulting in an impressive reduction or even disappearance of tumours (67% of mice cured) without causing any observable side effects.

开发能够在不伤害正常组织的情况下损伤肿瘤细胞的新治疗策略是化疗的主要障碍之一。在这项研究中，设计并合成了一种新型的 β-葡萄糖醛酸酶敏感性白蛋白结合前药，以选择性地将药物 SN38 递送至肿瘤部位并使其功效最大化。静脉给药后，前药 Mal-glu-SN38 通过迈克尔加成与血浆白蛋白共价结合，使其能够在肿瘤中积累并在细胞外 β-葡萄糖醛酸酶触发时释放 SN38。与伊立替康相比，Mal-glu-SN38 显示出较慢的血浆清除率和随时间增加的药物暴露。此外，与伊立替康相比，Mal-glu-SN38 导致白蛋白-前药偶联物和从白蛋白偶联物释放的游离 SN38 的肿瘤部位积累增加。